Biologics in Rheumatology New Developments, Clinical Uses and Health Implication 2016

NEW DEVELOPMENTS IN MEDICAL RESEARCH

BIOLOGICS IN RHEUMATOLOGY NEW DEVELOPMENTS, CLINICAL USES AND HEALTH IMPLICATIONS

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NEW DEVELOPMENTS IN MEDICAL RESEARCH

BIOLOGICS IN RHEUMATOLOGY NEW DEVELOPMENTS, CLINICAL USES AND HEALTH IMPLICATIONS

COZIANA CIURTIN, PHD FRCP AND

DAVID A. ISENBERG, MD FRCP FAMS EDITORS

New York

Copyright © 2016 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470 E-mail: [email protected]. NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data ISBN: 978-1-63485-302-6 (e-book) LCCN: 2016939407

Published by Nova Science Publishers, Inc. † New York

CONTENTS Preface

ix

Biologic Treatments in Autoimmune Rheumatic Diseases

1

Chapter 1

Biologic Therapies for Systemic Lupus Erythematosus Maria Mouyis, Coziana Ciurtin and David A. Isenberg

Chapter 2

Biologics in Juvenile Systemic Lupus Erythematosus Claire-Louise Murphy and Nicola Ambrose

33

Chapter 3

Biologic Treatments for Idiopathic Inflammatory Myopathies Serena Fasano and David A. Isenberg

45

Chapter 4

Biologic Treatment Advances in Sjӧgren’s Syndrome: Understanding the Implications of Using Biologic Therapies in Selected Categories of Patients Coziana Ciurtin, Nicolyn Thompson and David A. Isenberg

3

57

Chapter 5

Biologic Therapies in Systemic Sclerosis Svetlana I. Nihtyanova and Christopher P. Denton

Chapter 6

The Role of Biologics in the Treatment of Small and Medium Vessel Vasculitis Lubna Ghani and Eleana Ntatsaki

109

Imaging and Pathogenesis in Large Vessel Vasculitis: Early Lessons for Biologic Treatments Philip P. Stapleton, Katerina Achilleos, Dimos Merinopoulos and Bhaskar Dasgupta

145

Biologics in Behçet Syndrome Emon Khan

177

Chapter 7

Chapter 8

83

vi

Contents

Biologic Treatments in Chronic Inflammation Arthritides Chapter 9

Tumour Necrosis Factor Inhibitors Used in the Treatment of Rheumatoid Arthritis: Evidence of Safety, Efficacy and Health Implication Katie Bechman, Laura Attipoe and Coziana Ciurtin

197

199

Biologic Treatments (Other than Anti-TNF Therapy) Licensed for Use in Rheumatoid Arthritis Laura Attipoe, Katie Bechman and Coziana Ciurtin

229

New Biologic Agents and Biosimilars Developed for Rheumatoid Arthritis Laura Attipoe, Katie Bechman and Coziana Ciurtin

259

Chapter 12

Biologics in Spondyloarthritis Mediola Ismajli and Maria Leandro

283

Chapter 13

Established and New Biologic Therapies for Psoriatic Arthritis and Psoriasis Benjamin J Thomas, Sarah Elyoussfi and Coziana Ciurtin

307

Biologics in Juvenile Idiopathic Arthritis Charalampia Papadopoulou and Nicola Ambrose

347

Chapter 10

Chapter 11

Chapter 14

Miscellanea

375 Biologic Disease Modifying Anti-Rheumatic Drugs in Pregnancy and Breast-Feeding Period Hanh Nguyen and Ian Giles

377

Biologic Therapy in Osteoporosis: New Developments, Clinical Uses and Health Implications Maria Mouyis and Judith Bubbear

405

Biologic Treatments for Pulmonary Involvement in Rheumatic Disease Helen S. Garthwaite and Joanna C. Porter

425

Chapter 18

Additional Benefits of Tumour Necrosis Factor Inhibitor Therapies Angela Pakozdi and Vanessa Morris

449

Chapter 19

Infection and Biologics Maria Krutikov and Jessica Manson

465

Chapter 20

Participant Information Sheets in Clinical Research: Compromising the Ethics of Informed Consent? Andra F. Negoescu, Leslie Gelling and Andrew J. K. Östör

495

Biologic Treatment: The Young Patients’ Perspective Nicola Daly

501

Chapter 15

Chapter 16

Chapter 17

Chapter 21

Contents Chapter 22

Strategies and Safety Nets: Nurse-Led Care of the Patient on Biologics Pauline Buck and Victoria Howard

vii

507

About the Editors

521

Index

523

PREFACE Significant progress has recently been achieved in the treatment of many autoimmune rheumatic diseases (ARD) with the introduction of biologic treatments, which target specific molecules implicated in their pathogenesis. In the past two decades, these developments have substantially improved the long-term outcome of patients with ARD, both in terms of their survival rates and quality of life. The principal biologic approaches in clinical use include biologic agents that (a) interfere with cytokine function, (b) inhibit the “co-stimulatory signal” required for T cell activation and (c) deplete the circulatory B cells. The first rheumatic condition that benefitted from the introduction of the biologic agents was rheumatoid arthritis, and following the great therapeutic success of this approach, the majority were subsequently tested in other autoimmune diseases. More recently, new biologic agents have emerged that are tailored to the immune abnormalities characteristic of a particular ARD. Apart from discussing the established and newly developed biologic therapies, this book also reviews the small molecule inhibitors licensed or tested in different rheumatic diseases. This book is a collaborative effort on the part of many rheumatologists in the UK, which critically appraises the level of evidence behind the use of biologic agents in diverse rheumatic conditions. The profound effects on long-term health and less commonly explored aspects of the use of biologics are also addressed in different chapters of the book. The established and newly developed biologic drugs are reviewed in separate chapters focusing on rheumatoid arthritis, systemic lupus erythematosus, myositis, systemic sclerosis, Sjӧgren’s syndrome, seronegative spondyloarthropathies, psoriatic arthritis and psoriasis, small, medium and large vessel vasculitis (including a separate chapter on Behçet’s disease), osteoporosis and interstitial lung disease associated with rheumatic conditions. In addition, in the second section of the book, miscellaneous aspects of the benefits of biologic therapies from adult and adolescent rheumatology nurse perspectives can be found, together with a discussion of ethical issues related to consenting patients for in clinical trials with biologic drugs. Furthermore, we have also included chapters which explore the infection risk associated with the use of each class of biologics. Another chapter has been dedicated to the use of these drugs during pregnancy and breast-feeding. The book is aimed at a wide audience, including rheumatology specialists, trainees and nurses. In order to help guide health professionals with their therapeutic choices, aspects of the cost-effectiveness of different biologic therapies, together with national and international

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Coziana Ciurtin and David A. Isenberg

guidelines supporting their use in the rheumatic diseases are discussed in detail for every licensed biologic therapy. We hope that readers who are interested in improving their knowledge about the recent advances in the use of biologic treatments in rheumatic diseases will find this book helpful.

Dr. Coziana Ciurtin, PhD FRCP University College London, UK Prof. David A. Isenberg, MD FRCP FAMS Academic Director of Rheumatology University College London, UK

BIOLOGIC TREATMENTS IN AUTOIMMUNE RHEUMATIC DISEASES

In: Biologics in Rheumatology Editors: Coziana Ciurtin and David A. Isenberg

ISBN: 978-1-63485-274-6 © 2016 Nova Science Publishers, Inc.

Chapter 1

BIOLOGIC THERAPIES FOR SYSTEMIC LUPUS ERYTHEMATOSUS Maria Mouyis1, MRCP, Coziana Ciurtin2,3, PhD FRCP and David A. Isenberg2,3, MD FRCP FAMS Department of Rheumatology, Northwick Park Hospital, London, UK 2 Department of Rheumatology, University College London Hospital NHS Foundation Trust, London, UK 3 Centre for Rheumatology, Department of Medicine, University College London, London, UK 1

ABSTRACT Advances in molecular biology have led to the development of biologic therapies. This is particularly relevant in systemic lupus erythematosus (SLE), which is a multisystem autoimmune rheumatic disease (ARD) associated with potentially lifethreatening complications if not adequately treated. The availability of new biologic drugs has improved the prognosis of SLE in selected cases associated with unsatisfactory response to conventional therapies. Over the last decade, there have been developments in the availability of biologic agents for SLE treatment based upon the advances in the understanding of the disease pathogenesis. Even if the evidence of biologic treatment efficacy in SLE is weaker than in other autoimmune rheumatic diseases, such as rheumatoid arthritis (RA), significant progress was made, as the first biologic treatment for use in SLE patients received approval in 2011. These new biologic therapies for SLE range from anti-CD20/CD22 (clusters of differentiation characteristic to B cells), to antiB cell activating factors and anti-interferon alpha (IFNα). This chapter reviews the various biologic agents used in SLE, their mechanism of action and safety profile. The most common side effects to biologic treatments include infection, tuberculosis (TB) reactivation and allergic reactions. Less common side effects include development of 

Correspondence to: Prof. David A Isenberg, Academic Director of Rheumatology, Centre for Rheumatology, 424 The Rayne Institute, 5 University Street, University College London, London, WC1E 6JF, UK, email: [email protected].

4

Maria Mouyis, Coziana Ciurtin and David A. Isenberg lymphoma and anti-drug or autoimmune antibody formation. Despite their toxicity profile, biologic agents are gaining ground in clinical practice, due to the limited efficacy or increased toxicity of conventional disease modifying agents (DMARDs). Biologic therapies targeting B cells, such as rituximab, and B cell activation factors, such as belimumab, are currently used in the treatment of refractory SLE. Furthermore, aggressive treatment, including the use of biologic agents, reduces long-term complications associated with prolonged use of steroids in SLE, such as cardiovascular disease and osteoporosis. In the short term, the biologic agents are expensive when compared to traditional DMARDs; however, there is evidence that their use is associated with long term benefits for patients with SLE, such as reduced hospital admission and disease complications, and improved patient outcomes. This chapter provides a summary of most biologic agents tested in SLE patients, considering their efficacy and safety profile, as well as the health implications associated with their use. We also take a brief look at newer agents currently investigated in clinical trials.

Keywords: systemic lupus erythematosus, biologic treatments, safety, efficacy, biosimilars

INTRODUCTION SLE is a complex ARD characterised by clinical manifestations that range from mild to severe. For many years the main treatments used were the traditional DMARDs, such as hydroxycholorquine, azathioprine, cyclophosphamide, methotrexate and mycophenolate mofetil (MMF). Unfortunately, these therapeutic agents have increased toxicity or, in some cases, limited efficacy in controlling the complex symptoms of this disease. Despite the progress made in optimising the treatment of severe disease manifestations (e.g., lupus nephritis), the long-term prognosis of this disease has not changed dramatically in the last 30 years [1]. Patients with SLE are often treated for many years with prednisolone, which provides an additional array of complications, such as hypertension, glaucoma, steroid induced diabetes and osteoporosis. Although the treatment of SLE has, on the whole, improved lupus outcomes, less success was achieved in preventing or addressing the increased morbidity of this condition [2-4]. The availability of biologic agents is leading to a new treatment era for SLE patients, and there is hope for a better therapeutic management in the future.

PATHOGENESIS A deeper understanding of the pathogenesis of SLE facilitated the discovery and development of many biologic agents targeting various molecules or receptors [5]. The correlation between different cellular and molecular players (identified as key factors in lupus pathogenesis) and the available biologic therapies targeting the abnormalities associated with lupus are illustrated in Figure 1. SLE is largely a B cell driven phenomenon with interplay between genetic, hormonal and environmental factors [6]. External triggers, such as ultraviolet (UV) radiation or Ebstein-Barr virus (EBV) infection, in conjunction with a maladaptive immune system and altered epigenetics are known to lead to the accumulation of apoptotic nuclear debris, comprising anti-double

Biologic Therapies for Systemic Lupus Erythematosus

5

stranded DNA (dsDNA) fragments and RNA antigens [7-9]. The debris is then processed by B cells, which function as antigen presenting cells (APC). This process then precipitates the formation of antibody production and the release of pro-inflammatory cytokines, such as interleukin (IL) 6, IL10, interferon γ (IFNγ), B lymphocytes stimulator/a proliferationinducing ligand (BLyS/APRIL) and tumour necrosis factor alpha (TNFα). These cytokines promote auto B cell and auto T cell activation leading to a sustained inflammatory response [10]. T cells are important in the homeostatic control of the B cell responses. In SLE patients T cells are dysregulated. T1 helper cells are overexpressed and release significant amounts of IL12, IL18 and IFNγ. T2 helper cells are not overexpressed in comparison to T1 helper cells, but they secrete increased IL10 levels [11, 12]. There is also a decreased production in IL2 levels [13]. Regulatory T cells (Tregs), which are meant to dampen the pro-inflammatory T cell profile, are suppressed in SLE [14].

Legend: APRIL - a proliferation-inducing ligand; BAFF – B cell activating factor; BlyS - B lymphocytes stimulator; CD20 – cluster of differentiation 20 marker expressed from late pro-B cells through memory cells, but not on either early pro-B cells or plasma blasts and plasma cells; CD22 – cluster of differentiation 22 found on the surface of mature B cells and to a lesser extent on some immature B cells; CD80 – cluster of differentiation 80 is a protein found on activated B cells and monocytes that provides a costimulatory signal necessary for T cell activation and survival; IL – interleukin. Figure 1. Schematic presentation of targeted therapy of SLE.

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Maria Mouyis, Coziana Ciurtin and David A. Isenberg

Furthermore, there are changes in signalling subunits on the T cell receptors which lead to an increase production of co-stimulatory molecules, such as cluster of differentiation 40 ligand (CD40L) [15]. The role of T cells in SLE is still being researched and new target biologic therapies are currently explored. Another pathogenic process associated with lupus is the formation and deposition of immune complexes [16]. In SLE there is a failure of clearing immune complexes leading to immune complex deposition in organs such as kidneys or blood vessels, causing inflammation and tissue injury [17]. Every aspect of the immune abnormalities associated with lupus can be theoretically explored for therapeutic purposes. Progress has been achieved in testing different experimental biologic drugs. Recently, belimumab, an anti B cell activating factor (BAFF) therapy, became the first biologic treatment ever approved by Food and Drug Administration agency (FDA) for use in SLE patients, and the only treatment for lupus approved in over 50 years. It has also been approved for use in SLE patients in Europe, Middle East and Africa. Despite the impressive advances in molecular biology and drug technology, this complex autoimmune disease is still associated with increased morbidity and mortality. New treatment options are continuously explored to address the unmet need of a better quality of life and outcomes for patients (Figure 1).

BIOLOGIC THERAPIES The biologic therapies, currently in use or under development for lupus, target B cells, T cells, IFNα, IL6, and fusion proteins. This chapter explores the main biologic therapies available for the treatment of SLE patients, including the agents currently under investigation, detailing their mechanism of action, side effects and dosages. The level of evidence of efficacy and safety related to the efficacy of these biologic agents is summarised in Table 1. Table 1. An overview of biologic therapy in SLE Biologic Trial Agent B-cell depleting agents: Rituximab EXPLORER LUNAR

Ofatumumab

Mechanism of action

Side effects

Dosage

Organ specific indication

Anti-CD20 chimeric monoclonal antibody

Infusion reaction Increased infection risk PML Lymphoma

1 g IV twice, 2 weeks apart

SLE nephritis Non-renal SLE (despite negative RCTs results)

RA trials. Fully human Case reports in monoclonal SLE. antibody…

Infusion reactions Urticaria Rash Rhinitis Nausea

375 mg/m2 IV every 4 weeks 750 mg cyclophosphamide may be given with the first infusion to increase B cell depletion effect 300, 700, 1000 mg IV every 2 weeks for 24 weeks.

Arthritis (RA) ?SLE

7

Biologic Therapies for Systemic Lupus Erythematosus Biologic Agent Ofatumumab

Ocrelizumab

Trial

Mechanism of action RA trials. … against Case reports in membrane SLE. proximal epitope on CD20 molecule Phase III trials Fully human in SLE monoclonal antibody against CD20

Anti-B-cell activating factors Epratuzumab EMBODY-1 EMBODY-2

Belimumab

BLISS 52 BLISS 76

Tabalumab

IILUMINATE

Blisibimod

Phase II PEARL-SC

Atacicept

Phase II APRIL-SLE (terminated) Phase II ADDRESS-II (ongoing)

IgG1 monoclonal antibody against the CD22 molecule Human monoclonal immunoglobuli n (IgG1y) against BAFF/BLySS.

Side effects

Dosage

URTI Headaches Fatigue Flushing

300, 700, 1000 mg IV every 2 weeks for 24 weeks.

Severe infections (increased in patients treated with MMF)

400 mg or 1,000 mg SLE nephritis ocrelizumab, given as an IV infusion on days 1 and 15, followed by a single infusion at week 16 and every 16 weeks thereafter

Infusion reaction, URTI’s Fever Headache Nausea and dizziness

600 mg IV every week for four weeks or 1,200 mg IV every two weeks for four weeks

Nausea Diarrhoea Headaches URTI Fever Cystitis Infusion reaction Human URTI monoclonal UTI antibody Injection site against BAFF reactions Myocardial infarct Discitis Osteomyelitis Breast cancer Cerebrovascular accident Pulmonary fibrosis Fusion protein, Injection site selective reactions antagonist of BAFF TACI-Ig LRTI/URTI fusion protein Injection site that inhibits reaction BLyS and Fever APRIL Arthralgia Sinusitis Headache Fatigue Rhinitis Dizziness Depression

Organ specific indication Arthritis (RA) ?SLE

Neuropsychiatric, muco-cutaneous and musculoskeletal SLE manifestations. 10 mg/kg IV every 2 Non renal SLE weeks x 3 and then once Non cerebral every 4 weeks SLE

240 mg SC loading dose, followed by 120 mg SC every 2 or 4 weeks

Non-renal SLE Non-cerebral SLE

200 mg weekly

Non-renal SLE Non-cerebral SLE

75 mg or 150 mg SC weekly

SLE nephritisstudy terminated because of sideeffects.

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Maria Mouyis, Coziana Ciurtin and David A. Isenberg Table 1. (Continued)

Biologic Trial Agent Anti-IFN alpha Sifalimumab Phase III trial

Rontalizumab Phase II trial

Blockade of T cell activation Abatacept Phase III trials

Mechanism of action

Side effects

Dosage

Organ specific indication

Infusion reaction Fatigue URTI UTI Sinusitis Dizziness Arthralgia Headache Lymphopenia Anaemia A recombinant Viral infections humanised Reactivation of monoclonal Herpes infection antibody to Sinusitis IFNα Bronchitis

0.3, 1.0, 3.0, or 10.0 mg/kg IV- still undergoing trials

SLE nephritis

750 mg IV 4 weekly 300 mg SC 2 weekly 0.3-10 mg/kg

Moderate-severe SLE

Human IgG1 heavy chain fused with CTLA4 that blocks T cell activation by B cells.

10-30 mg/kg IV

Discoid SLE Arthritis Serositis

IFNα monoclonal antibody

Nausea Headache Infusion reaction Fever Hypertension Back pain Infections

IL6 inhibition Tocilizumab RA trials Phase 1 SLE trials

Monoclonal URTI 4 or 8 mg/kg IV SLE nephritis IgG1 antibody GI infections SLE with to IL6 receptor TB moderate GI perforation activity Non-melanoma skin tumours Malignancies Abnormal LFT High cholesterol levels Suppression of CRP Legend: CRP - C reactive protein; CTLA4 - cytotoxic T-lymphocyte-associated protein 4; GI - gastro-intestinal; IFR - individual funding request form, IFN - interferon; Ig - immunoglobulin; IL - interleukin, IV intravenous; LFT - liver function tests; LRTI - lower respiratory tract infection; MMF - mycophenolate mofetil; PML - progressive multifocal leukoencephalopathy; RA - rheumatoid arthritis; RCT - randomised controlled trial; SC - subcutaneous, SLE - systemic lupus erythematosus, TB - tuberculosis; URTI - upper respiratory tract infection; UTI - urinary tract infection.

Advantages and Disadvantages The advantages of biologic therapies compared with some of the conventional therapies used for moderate-severe manifestations of SLE include potential efficacy in terms of disease control and relative safety in pregnancy, especially when compared to methotrexate, MMF

Biologic Therapies for Systemic Lupus Erythematosus

9

and cyclophosphamide, which are contraindicated in pregnancy. The biggest disadvantage of both, biologic and non-biologic DMARDs, is that of immunosuppression, which is associated with increased risk of infection. Patients treated with biologics have to be screened for TB and hepatitis, as both infections can reactivate during the biologic therapy administration. A more significant concern, with most biologic agents, is the risk of progressive multifocal leukoencephalopathy (PML). This is not a drug specific phenomenon; although extremely rare, it is associated with significant mortality [18]. Another concern is that of the cost of biologic therapies. Biologic agents are expensive as they are manufactured through advanced processes of biotechnology and genetic engineering. However, the cost of treatment needs to be compared to the cost of having to manage all the challenging aspects of the disease. SLE patients in general utilise more health resources according to the severity of their disease and age at diagnosis, and patients with active lupus nephritis or regular flares even more so than a patient with mild or quiescent disease [19-21]. The cost of a patient having SLE includes direct and indirect costs [22]. The indirect costs are related to an individual’s quality of life and ability to work [23]. The cost of an individual’s loss of work on average in the US is was estimated at approximatively $16,345 per year in 2011 [19]. About 10 years ago, direct costs were assessed in a tri-nation study, which evaluated patients with SLE from several tertiary centres in Canada, US and UK respectively [24]. The direct cost of lupus treatment, including productivity over a 1 year period, was approximately $20,000 in the US [24]. There were also significant differences of the health system indirect costs in different countries [25, 26], and differences in the access of patients with lupus to the health care system across the world [27, 28]. A study from 2008 estimated that the annual (direct and productivity) cost for patients with lupus of employment age was $20,924 [23]. The cost of rituximab is approximately £4000 for two infusions in the UK, and there are data suggesting the cost-saving potential of rituximab in the management of lupus nephritis [29]. With the advent of biosimilars, the cost of treating SLE may become cheaper, but the efficacy of biosimilars (arguably having similar properties to the “original” biologic treatment) has yet to be proven [30, 31]. In the context of discussing the costeffectiveness of biologic treatments it is worth mentioning that another advantage of the use of biologic agents is the intravenous (IV) administration of some of the available agents, which improves patient compliance and adherence to medication. New therapies, such as atacicept are already available as subcutaneous (SC) injections; therefore, the above advantage might be lost for some of biologic therapeutic options. On the other hand, preserving the patient independence and enabling them to self-administer injectable treatments can contribute in itself to the reduction of additional health care costs. A study from 1991 by Petri et al. reported poorer adherence amongst Afro-Caribbean patients leading to more significant renal SLE and indirect increase in the healthcare costs [32]. Ultimately, the cost of treatment needs to be balanced against the economic cost of disease for a realistic estimate of the cost-efficacy of different biologic therapeutic options. The use of biologic agents in different countries is highly variable. In countries with poorer economic status, the access to expensive treatment options is limited and not always fairly distributed in the population. Mortality in lupus was associated with lower education, shorter duration of follow up and poor medical coverage in a large study from South American countries [33]. Belimumab is licensed for use to treat SLE in the US, Europe, but in the UK, the funding of the treatment is based on an individual funding request (IFR). The disparity between the

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Maria Mouyis, Coziana Ciurtin and David A. Isenberg

outcome of patients with lupus nephritis with private vs. public health insurance in US is well recognised [27, 34]. Belimumab has just been approved (July 2016) by NICE (National Institute of Clinical Excellence) in the UK having previously considered too expensive based on the QALY (quality-adjusted life year) calculations. Real life experience has shown some clinical benefits in patients with skin and joint manifestations [35]. Arguably QALY, which aims to appreciate the disease burden by taking into consideration both, the quality and duration of life, is a flawed measurement tool in the healthcare system [36]. An ideal system treatment for SLE would ensure an increased good quality life span at the lowest possible health care cost. This challenge is compounded by the dilemma of using biosimilars, which supposedly have similar efficacy as the biologic agents and the advantage of lower cost. However, data regarding the efficacy of biosimilars in head-to-head clinical trials aiming to compare them with the original biologic agent are missing for the majority of available options. Table 1 summarises the most studied biologic treatments in patients with lupus, with particular emphasis on their efficacy for certain SLE manifestations, dosage and toxicity profile.

Biologic Therapies Affecting B Cells 1. Anti-CD20 - rituximab, ofatumumab, ocrelizumab, veltuzumab 2. Anti-CD22 - epratuzumab Rituximab Mechanism of Action and Dosage Rituximab is a chimeric/humanised monoclonal antibody against CD20. It was the first biologic to be used in the treatment of SLE. The drug depletes CD20 B lymphocytes. The CD20 antigen is found on pre - B cells which would then form mature B cells [37]. Depletion of the B cell therefore reduces cell apoptosis and complement activation [38, 39]. Although the function of CD20 is unknown, it is considered that it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing differentiation and activation of B cells. The fragment antigen binding (Fab) domain of rituximab binds to the CD20 antigen on B lymphocytes, and the fragment crystallisable (Fc) domain recruits immune effector functions to mediate B cell lysis in vitro; in addition, rituximab increases the expression of major histocompatibility complex II (MHC II), and lymphocyte function-associated antigens 1 and 3 (LFA-1, LFA-3), triggers shedding of CD23, down-regulates B cell receptor and induces the apoptosis of CD20 B cells [40]. The standard dose currently recommended for the treatment of SLE is 1 g of IV rituximab given 2 weeks apart. Each dose is preceded by premedication with methylprednisolone, antihistamine and paracetamol to reduce the risk of infusion reactions. Cyclophosphamide may also be given pre-first dose to increase the efficacy of rituximab and enhance B cell depletion [41].

Biologic Therapies for Systemic Lupus Erythematosus

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Efficacy and Side Effect Profile Rituximab is considered effective in treating refractory SLE, although two large trials, LUNAR (clinical trial of patients with lupus nephritis) and EXPLORER (clinical trial which included non-renal patients) did not meet their primary endpoints. The reason for this is likely related to the concomitant use of high dose of steroids and concomitant conventional immunosuppressant therapy [42, 43]. However, some significant clinical and serological results were noted (e.g., significant reduction in proteinuria, lower steroid requirement, etc.). Despite the failure of these clinical trials, numerous case-reports and studies using rituximab off-label in lupus patients have shown a 70-90% response rate [43-46]. The role of rituximab as a steroid sparing agent has also become evident. Condon et al. reported results on 50 lupus nephritis patients treated with 1 g of rituximab 2 weeks apart and 500 mg of IV methylprednisolone [47]. No oral steroids were given and MMF was used as maintenance therapy. 70% (n = 36) of the patients achieved remission in a mean time of 36 weeks. The conclusion of the researchers was that oral steroids can be avoided (only 2/50 patients required them in a 2 year follow up period), and B cell depletion might be considered early in the treatment of lupus nephritis and other systemic manifestations of SLE. Rituximab minimised the need for additional steroids and was effective in ensuring a better long term control of the disease. An earlier, albeit smaller study of eight newly diagnosed rituximab treated patients (each case carefully matched to three conservatively treated patients) reported similar steroid sparing capacity of rituximab in non-renal lupus patients [48]. An international trial comparing rituximab and MMF in lupus nephritis patients treated with minimal dose of steroids vs. standard therapy with high doses of steroids and MMF (the RITUXILUP study) is currently undergoing and should provide more definitive answers regarding the exciting possibility to treat patients with lupus with low doses of steroids and rituximab. Side-effects of rituximab include infusion reactions, as documented in the initial oncology studies [49]. The most common side-effects are fever, bronchospasm, rash and hypotension, which usually settle on stopping the infusion. Patients are usually followed up carefully post-rituximab treatment to monitor for the development of common bacterial and viral infections, or other infections, such as TB and hepatitis B or C. Based on the experience acquired from treating RA patients with rituximab, this biologic agent is considered reasonably safe in the context of history of TB [50, 51]. There are reports of both reactivation of hepatitis B following treatment with rituximab [52], as well as effective treatment of vasculitis associated with hepatitis C with rituximab [53, 54]. Human anti chimeric antibodies have also been reported [55], and side-effects to medication are considered to be linked to the immunogenicity of these antibodies [56]. The effect of B cell depletion lasts for 6-12 months in about 75% of cases, and the response to therapy is variable [38, 57, 58], and, as shown recently, the longer the duration of B cell depletion, the better the outcome [59]. The process of B cell repopulation following B cell depletion therapy with rituximab in lupus is still not fully understood [60]. For safety reasons, it is recommended to check immunoglobulin (Ig) levels and CD19+ B cell count every 2 months until B cells normalise, as accumulated doses of rituximab may also cause hypogammaglobulinaemia which may be linked to an increased the risk of infection [61, 62]. The expert consensus is that rituximab is a safe and effective treatment option for patients with refractory renal and non-renal lupus and can reduce significantly the steroid burden [48, 63-65], despite the negative trial results.

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Maria Mouyis, Coziana Ciurtin and David A. Isenberg

Ofatumumab Mechanism of Action and Dosage Ofatumumab is a fully human monoclonal antibody anti-CD20 [66]. The treatment is licensed for use in patients with chronic lymphocytic leukaemia based on its proven efficacy in treating refractory cases [67, 68]. Most studies assessing dosing regimens in patients with rheumatic conditions have been done in RA patients, in whom the treatment was also associated with clinical benefit [69, 70]. The current recommended dose is 700 mg IV every 2 weeks. Similarly with other biologic agents, premedication is administered beforehand, to minimise the risk of infusion reactions [71]. Efficacy and Side Effect Profile The safety profile and efficacy of ofatumumab has also been established in a few RA clinical trials [69, 71]. The drug has been proved effective as B cell depletion agents as was associated with significant clinical improvement of symptoms of arthritis at different doses [71]. The pharmacokinetic of the medication was found similar in chronic lymphocytic leukaemia and RA [72]. A recent case report has suggested some benefit in the treatment of SLE [73]. Although safety profiles were established in phase 1 and II trials, the most comprehensive information related to the drug’s safety profile was provided by a phase III clinical trial in RA [69]. The most common side-effects were rash (21%) and urticaria (12%), which mostly occurred on the day of first infusion and they declined significantly with the second course. Most adverse events were of mild or moderate intensity (see Table 1). Ocrelizumab Mechanism of Action and Dosage Ocrelizumab is another fully human monoclonal antibody against CD20, developed for RA, SLE, and B cell derived malignancies [74, 75], which was tested for efficacy in patients with lupus nephritis [76]. The doses used in the largest phase III clinical trial were 400 mg or 1,000 mg ocrelizumab, given as an IV infusion on days 1 and 15, followed by a single infusion at week 16 and every 16 weeks thereafter [76]. Efficacy and Side Effect Profile Despite reaching an overall response rate of 66-67% in the ocrelizumab treatment arm, the difference in response vs. standard of care treatment did not reach statistical significance [76]. The study was terminated earlier as there was an infection-related safety signal in relation with increased risk of opportunistic and fatal infections in the ocrelizumab treatment groups [77]. The proportion of patients experiencing serious infections was twice as high in patients who received concomitant treatment with MMF (32% vs. 16% in the placebo arm), and it was increased in Asian patients [76]. Although ocrelizumab has been unsuccessful in one clinical trial in SLE, this negative result may be attributed to the use of concomitant MMF. It has also been trialed in relapsing and remitting multiple sclerosis with only 3 of 55 patients experiencing significant adverse events. The treatment was associated with a reduction in neurological lesions on magnetic

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resonance imaging (MRI) [78]. It remains possible that this drug can still be used in SLE pending additional trials.

Veltuzumab Mechanism of Action and Dosage Veltuzumab is a second generation humanised anti CD20 monoclonal antibody with a SC formulation, developed for the treatment of refractory pemphigus vulgaris and hematologic malignancies [79, 80]. A case report showed improved serological outcome with treatment with veltuzumab in a lupus patient who developed anti - drug antibodies (HACA) to rituximab [81]. The role of veltuzumab in SLE has yet to be clearly determined but may be used where rituximab is ineffective or there is “resistance”, as seen in patients with nonHodgkin lymphoma (NHL) [82]. Bispecific Monoclonal Antibodies Recent laboratory studies suggested that the use of bispecific antibodies (anti CD22/ CD20) might be effective in the treatment of lupus, as they were associated with increased trogocytosis. Trogocytosis is a process whereby lymphocytes conjugated with APC extract surface molecules from APCs and express them on their own surface in vitro, resulting in decreased levels of B cell surface markers associated with considerably less B cell depletion and therefore less risk of severe immunosuppression [83].

Epratuzumab Mechanism of Action and Dosage CD22 is a B cell transmembrane glycoprotein that is found on mature B cells. Epratuzumab is an IgG1 monoclonal antibody against the CD22 molecule, which inhibits B cell receptor activation and leads to subsequent B cell apoptosis. The ALLEVIATE-1 and ALLEVIATE-2 randomised clinical trials (RCTs) proved that 360 mg/m2 IV dose was more effective than the 720 mg/m2 IV dose as a steroid-sparing medication in patients with severe lupus. The responses correlated with improvements in health-related quality of life [84]. The EMBLEM study was an early phase II B study performed to determine the effective dose regimen in patients with moderate-severe lupus, which showed that patients receiving a total of 2400 mg had significant improvement in the disease activity [85]. The phase III studies, EMBODY 1 and 2, enrolled SLE patients who received placebo or treatment with 2400 mg of epratuzumab over four 12-week treatment cycles, administered as 600 mg every week for four weeks or 1,200 mg every two weeks for four weeks. The primary endpoint of both studies (which was defined as the percentage of patients meeting treatment response criteria at week 48 according to the British Isles Lupus Assessment Group (BILAG) - based Combined Lupus Assessment - BICLA) was not met and the research program was discontinued. BICLA, like the SRI (SLE responder index) system, requires patients to meet response criteria across three assessment tools: the BILAG-2004 index, SLEDAI index (SLEdisease activity index) and a physician’s global assessment (PGA).

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Maria Mouyis, Coziana Ciurtin and David A. Isenberg

Epratuzumab is considered to reduce on average only 35% of circulating B cells in patients, and has minimal antibody and complement-dependent cellular cytotoxicity (when evaluated in vitro), and it was hypothesised that its therapeutic activity may not result completely from B cell depletion [83]. However, this was not translated in clinical benefits.

Side Effect Profile Epratuzumab has been used in the treatment of both SLE and Sjögren’s syndrome [8587]. The drug has been proven to reduce BILAG scores, as well as neuropsychiatric (62.5%), muco-cutaneous (21.9%) and musculoskeletal symptoms (32%) compared to placebo [85]. Provisional encouraging results in SLE were not confirmed in a large phase III trial however. The common side effects included infusion reaction, upper respiratory tract infections (URTI’s), fever, headache, nausea and dizziness. A small proportion of patients developed human antidrug antibodies (HAHA). In contrast to rituximab, no severe decrease in the Ig levels was noted and this may be in relation to a partial depletion of B cells. Anti B Cell Activating Factors 1. Belimumab 2. Tabalumab 3. Atacicept Belimumab Mechanism of Action and Dosage This is a monoclonal humanised Ig which binds to the BLyS protein. It is a transmembrane protein expressed by T cells, dendritic cells and neutrophils. The BlyS protein binds to 3 receptors on the B cell surface: the B cell maturation antigen (BMCA), BAFFreceptor (BR3, BAFF-R) and a transmembrane activator and calcium modulating ligand interactor (TACI); via these receptors it has a role is in B cell differentiation, Ig production and levels of disease activity [88]. Patients with SLE have high levels of BlyS, therefore binding of the BlyS protein leads to decrease B cell activation, maturation and antibody production. The dose used in lupus clinical trials was 10 mg/kg IV every 2 weeks for 6 weeks and thereafter monthly. Efficacy and Side Effect Profile Belimumab is considered effective in patient with non-renal and non-cerebral SLE. FDA has approved it for mild to moderate SLE for those with skin and joint disease. It is not approved for active renal lupus or cerebral lupus. BLISS 52 and BLISS 76 studies have shown efficacy at 52 and 76 weeks [89]. BLISS 52 was carried out in countries from Central and Eastern Europe, Asia-Pacific, and Latin America. At 52 weeks, there was a 58% patients who had been treated with 10 m/kg of belimumab met the primary outcome, which was the SRI response rate (P = 0.017). SRI comprises criteria from three different internationally validated indices, SELENA-SLEDAI, PGA and BILAG 2004. BLISS 76 was a clinical trial which included patients from North America, and Western and Central Europe. Similarly, at week 52, 43% of patients treated with 10 mg/kg of belimumab met a similar primary outcome (p < 0.02). The 52 week response was not maintained at 76 weeks. The results of these large

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clinical trials suggested that improvement of disease control is more likely in patients with low C3 and high dsDNA levels [90]. A pooled post-hoc analysis of the combined phase III studies suggested a possible benefit in lupus nephritis as well [91]. Belimumab was associated with improvement of disease activity, reduced flares, decrease in dsDNA levels and low rate of side effects and it is currently licensed for use in non-renal lupus patients. The one drawback of belimumab is the delay onset of action and therefore, it is not ideal for an acute flare treatment. It can take up to 6 months to achieve 70% B cell depletion. Common side effects included nausea, diarrhoea, headaches and URTIs, but their frequency was low. The rates of patients experiencing adverse events, as assessed from pooled data from one phase II and two phase III RCTs were 16.6%, 19.5%, 13.5%, and 18.0% with placebo, and belimumab 1, 4, and 10 mg/kg, respectively [92]. There was also evidence of low rate of serious infusion reactions (including hypersensitivity reactions) occurring at a lower frequency that 1% in both placebo and active medication patient groups [92]. The side effect profile is not dose dependent. There is one case report of a severe delayed anaphylactic reaction which was fatal [92].

Tabalumab Mechanism of Action and Dosage BLyS, also known as BAFF, belongs to the TNF family. It is expressed by multiple cells including macrophages, monocytes, neutrophils and dendritic cells. BLys/BAFF binds to 3 receptors called BR3, thus affecting B cell lineage. TACI receptor is found on T cells and marginal zone B cells. BCMA (B cell maturation antigen) receptor is found on plasma cells. Activation of these receptors leads to auto-antibody production, increase in B cells and possibly potentiate malignancies [93]. In contrast to belimumab, tabalumab is an anti BAFF monoclonal antibody, which targets both membrane bound and soluble BAFF, currently used in RA [94]. The ILLUMINATE-1 study, a phase III RCT of tabalumab in patients with SLE, used the following dose regimen: 240 mg SC loading dose, followed by 120 mg every 2 weeks or 4 weeks in combination with traditional SLE treatments. The primary endpoint was the proportion of patients achieving an SLE Responder Index 5 (SRI-5) response at week 52. The SRI-5 is a composite endpoint defined as ≥5 point improvement (reduction) in SELENA-SLEDAI score, no new BILAG 2004 index score of A or no more than one new BILAG B score, and no worsening (increase ≥0.3 points from baseline) in PGA [95]. The study did not meet the primary endpoint. Similarly, no difference in the secondary outcomes (which included time to first severe SLE flare on the SELENA-SLEDAI Flare Index, proportion of patients with reduction in corticosteroid dose by ≥25% to ≤7.5 mg/day prednisone (or equivalent) for ≥3 consecutive months from weeks 24 through 52, and change from baseline on the Brief Fatigue Inventory at week 52), was found between the active and placebo groups. However, in a sensitivity analysis which did not exclude the patients who decreased antimalarial, steroid or immunosuppressant therapy, SRI-5 response was achieved with tabalumab 120 mg every 4 weeks (37.0% vs 29.8% placebo; p = 0.021), suggesting a potential for this biologic agent to be effective in selected categories of lupus patients [95]. Furthermore, the ILLUMINATE-2 study, which was set up in a broadly similar way to ILLUMINATE-1, but not excluding these patients whose concomitant medications were reduced, did not meet its primary endpoint.

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Maria Mouyis, Coziana Ciurtin and David A. Isenberg

Unfortunately, despite the encouraging results, Eli-Lilly have terminated the tabalumab program in lupus. Efficacy and Side Effect Profile The side-effects noted from the initial RA trials include infections and injection site reactions [96]. The most common infections included URTI and urinary tract infections (UTIs). Severe adverse events were also noted, such as myocardial infarct, discitis, osteomyelitis, breast cancer, cerebrovascular accident and pulmonary fibrosis [96, 97]. The treatment with tabalumab was associated with slight increase in the incidence of depression and suicidality compared to placebo in the ILLUMINATE-1 study, but these side-effects were uncommon [98]. The incidence of serious infections and severe infections were similar in the tabalumab and placebo groups in SLE patients [95].

Atacicept Mechanism of Action and Dosage This novel agent inhibits both BLyS and APRIL in B cells, affecting B cells ranging from immature to mature. It is a TACI-Ig fusion receptor protein [99]. As described above, by inhibiting BlyS and APRIL it causes a reduction in B cell proliferation, IFNγ and Ig production [100]. The doses used in the phase II/III RCT in lupus were either 75 mg or 150 mg atacicept SC biweekly for 4 weeks and then weekly versus placebo [101]. Efficacy and Side Effect Profile In the APRIL-SLE phase II RCT, the 150 mg atacicept arm was terminated early due to two fatal infections [101]. Despite this, a post-hoc analysis of atacicept 150 mg has shown that this dose regimen reduced the incidence of flares and time to first flare compared to placebo (flare rate 37% vs. 54%, odds ration - OR = 1.15 (0.73-1.8), and time to flare HR = 0.56, P = 0.009) [102]. There was no difference between atacicept 75 mg and placebo. The clinical response was accompanied by decrease in B cells, Ig levels and increase in complement levels. The 75 mg arm failed to meet the primary endpoint, defined as a significant decrease in the proportion of patients experiencing at least one flare of BILAG A or B [101]. The main safety concern regarding atacicept is that of potential increased incidence of hypogammaglobulinaemia and therefore risk of infection. A study in patients with lupus nephritis was terminated after the enrolment of only 6 patients because of the severe decreased in the level of Ig [103]. A closer look at the concomitant medication, showed that these patients’ hypogammaglobulinaemia developed when the patients were given MMF before they were treated with atacicept [104]. It was hypothesised that targeting APRIL in autoimmune disease might be associated with significant risk of toxicity [105]. Further phase II/III clinical trials of atacicept in lupus are currently undergoing (ADDRESS II) and should be able to provide additional information about the safety profile of this biologic agent. Apart from the two deaths encountered in the 150 mg atacicept group in the APRIL-SLE trial, the proportion of the serious infections was not statistically significantly different between the 75 mg atacicept arm when compared to placebo [101]. Furthermore, the death and injection rates were similar to those reported in the belimumab studies. The most common infections

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encountered included haemophilus influenzae pneumonia, legionella pneumonia and bacillus bacteraemia. Preclinical studies showed an increase in liver transaminases [101].

Blisibimod Mechanism of Action and Dosage Blisibimod is a fusion protein consisting of four BAFF binding domains fused to the Fc region of a human antibody, which acts as a selective antagonist of BAFF. Blisibimod selectively inhibits both soluble and membrane-bound BAFF. Efficacy and Side Effect Profile The efficacy and safety of blisibimod in subjects with SLE was investigated in a phase II RCT, PEARL-SC study, which found that the highest tested dose of 200 mg blisibimod administered SC once weekly was associated with increased SRI-5 response rates, but without reaching statistical significance when compared with placebo. The treatment was more effective in patients with SELENA-SLEDAI improvement of ≥8, and in a subgroup of patients with severe disease (SELENA-SLEDAI ≥10) [106]. Blisibimod was associated with a decrease in the number of naïve B cells (24-76%) and a transient relative increase in the memory B cell compartment in the phase 1 studies [107]. It was also associated with significant decrease of dsDNA, increase in the complement C3 and C4, and reductions in serum B cell levels in the PEARL-SC study [106]. Blisibimod is currently being tested in a phase III study for SLE, CHABLIS-SC1, and a phase II study, BRIGHT-SC, for IgA nephropathy. The treatment with blisibimod was safe, as the incidence of serious side-effects was similar to the placebo arm. Injection site reactions were reported more frequently with blisibimod compared with placebo, but they were mild (erythema) [106]. Taking into consideration this treatment’s serological benefits in SLE patients and acceptable safety profile, the results of the phase III study are awaited with interest as if proven more effective than belimumab, the treatment has a good chance to be the next licensed biologic treatment for lupus. Anti-Interferon Alpha (IFNα) 1. Sifalimumab 2. Rontalizumab 3. Anifrolumab Mechanism of Action Sifalimumab and rontalizumab are anti-IFNα monoclonal antibodies. An increase in BAFF occurs via signalling of INFα. The signalling pathway is activated by the stimulation of the IFN-1 receptor. In SLE pathogenesis there is activation of type 1 IFN, which is associated with lupus nephritis [108, 109]. Neutralisation of IFNα will lead to a reduction of inflammation by a reduction in BAFF levels, mature B cells, antibody production and T cell activation [110, 111].

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Maria Mouyis, Coziana Ciurtin and David A. Isenberg

Sifalimumab Dosage An optimal dose is yet to be confirmed as trials are currently underway. The phase I RCT in lupus used the following doses: 0.3, 1, 3, 10 or 30 mg/kg as a single IV administration [112]. The results of a promising phase II RCT of sifalimumab in SLE were presented at the 2014 American College of Rheumatology (ACR) annual meeting [113]. The patients were randomised to receive monthly IV doses of sifalimumab at 200, 600, or 1200 mg or placebo for 1 year based on their disease activity, IFN signatures and geographic region. The primary endpoint, defined as the percentage of patients achieving an SRI at day 365, was achieved in all the treatment active arms (sifalimumab 200, 600, and 1200 mg doses were associated with 58.3, 56.5, 59.8%, SRI response respectively, compared to 45.4% in the placebo group). Surprisingly, there were no significant changes of the dsDNA or complement levels despite the good response to treatment [113]. Efficacy and Side Effect Profile The results from the early phase clinical trials showed a reduction in SLE disease activity [108, 113], and phase 3 trials are currently underway. Sifalimumab is considered safe although there have been reports of increase incidence of herpes zoster infection. Other side effects typically include infusion reactions, nausea, URTIs, UTIs, headache and arthralgia [108, 114]. Rontalizumab Mechanism of Action and Dosage Rontalizumab has a similar mechanism of action as sifalimumab [109]. In an early phase, dose-escalation study, patients were enrolled into dose groups ranging from 0.3 to 10 mg/kg, administered via IV or SC routes [115]. Efficacy and Side Effect Profile A recent phase II studies with rontalizumab in lupus did not meet the criteria for efficacy which were reduction in disease activity as assessed by the BILAG and SRI [116]. A phase I study showed a dose dependent decrease in the level of IFNα, but no decrease in levels of dsDNA. The side effect profile was deemed similar to placebo, although an increase in viral infections was noted [115, 116] Anifrolumab Mechanism of Action and Dosage Anifrolumab is a type I IFN receptor antagonist [117], which was recently tested in a phase II RCT in patients with SLE using two dose regimens: 300 and 1000 mg IV anifrolumab, monthly administration (ACR abstract data, Merrill et al., 2015 in press).

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Efficacy and Side Effect Profile The primary endpoint of this phase II RCT of anifrolumab in patients with moderate to severe SLE was a composite SRI response at day 169 with sustained reduction of the steroid dose (